Current HIV-1 vaccine strategies are based on the assumption that persistent immune control will be possible, but the extent to which this occurs in natural infection is not known. Emerging data provide convincing evidence that the cellular immune system contributes to containing HIV replication. We now propose to build on the previous 15 years of this grant to perform a detailed analysis of immunologic, host genetic and viral factors associated with spontaneous control of viremia in a unique subset of HIV-infected persons who are able to achieve persistent viral control without antiviral therapy. Through a nationwide collaborative effort with academic institutions and primary care physicians, we will expand our existing cohort of 90 persons we term "controllers", namely persons who maintain viral loads of less than 2000 and often less than 50 RNA copies/ml plasma despite never having been treated with antiviral therapy. This cohort will provide a unique opportunity to determine the extent to which persistent immunologic control is possible in HIV infection, and the extent to which viral and host genetic factors contribute to long-term control of viremia. Comparison to a second cohort comprised of progressors with untreated infection and uncontrolled viremia, as well as longitudinal follow up to examine controllers who ultimately progress will provide the opportunity to determine the factors associated with control and loss of control of viremia. The results of these studies have critical implications not only for understanding HIV immunopathogenesis, but also for current vaccine strategies. Specifically, we propose to a) Establish a cohort of untreated HIV infected persons who control viremia and determine host and viral genetic factors associated with successful in vivo restriction of viral replication; b) Characterize the HLA allele-specific dominant and subdominant CD8 T cell responses associated with successful control of HIV viremia, and compare this to uncontrolled infection; and c) Determine the replicative fitness of clinical isolates collected from persons who spontaneously control viremia to investigate the role of viral attenuation in containment of HIV replication.